Polymorphisms of Antioxidant Genes as a Target for Diabetes Management

Diabetes mellitus (DM) is one of the most important health problems with increasing prevalence worldwide. Oxidative stress, a result of imbalance between reactive oxygen species (ROS) generation and antioxidant defense mechanisms has been demonstrated as the main pathology in DM. Hyperglycemia-induced ROS productions can induce oxidative stress through four major molecular mechanisms including the polyol pathway, advanced glycation end- products formation, activation of protein kinase C isoforms, and the hexosamine pathways. In the development of type 2 DM (T2DM) and its complications, genetic and environmental factors play important roles. Therefore, the aim of this review was to focus on the assessment of single-nucleotide polymorphisms within antioxidant enzymes including superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase, nitric oxide synthase, and NAD(P)H oxidase and their association with T2DM. The results would be helpful in understanding the mechanisms involved in pathogenesis of disease besides discovering new treatment approaches in management of DM.

Pathways influencing diabetes in association between reactive oxygen species and antioxidants. ROS: reactive oxygen species; SOD: superoxide dismutase; NOS: nitric oxide synthase; GPx: glutathione peroxidase; Nox: NAD(P)H oxidase; CAT: catalase; GST: glutathione-S-transferase; AGE: advanced glycation end-products, PKC: protein kinase C. role of oxidative stress in the initiation and development of diabetes complications has been determined (12). Generation of reactive oxygen species (ROS) secondary to hyperglycemia may lead to increased oxidative stress in β-cells which cause β-cell dysfunction and other long-term complications of diabetes because of insulin secretion and/or its function impairment (5,13).
Oxidative stress is defined as a disruption in balance between ROS and antioxidants produced upon oxidative damage (8,(11)(12)(13)(14). ROS includes a series of oxygen intermediates such as superoxide anion, hydrogen peroxide, hydroxyl radical, and hypochlorous acid (15). Although under normal physiological conditions, ROS could help in cell defense, hormone synthesis, signal transduction, transcription factor regulation, and gene expression, but under pathological conditions aberrant tissue damage, inflammation, fibrosis, and β-cell death can occur (13). The four major mechanisms involved in increased intracellular oxidative stress as a result of hyperglycemia, are polyol pathway, advanced glycation end-products (AGEs), protein kinase C (PKC)-diacylglycerol (DAG) and the hexosamine pathways (9,16). It has been shown that all of these pathways are activated by mitochondrial ROS overproduction (9) ( Figure   1). The effects of ROS can be modified by enzymatic or non-enzymatic antioxidants. Enzymatic

Polyol pathway
The polyol pathway uses NADPH and converts excessive intracellular glucose into forms of sugar alcohols through aldose reductase enzyme.
In non-diabetic subjects, this pathway utilizes very small fraction of total glucose. But in diabetics, aldose reductase is activated and induces increasing conversion of glucose to sorbitol. Then, sorbitol is oxidized to fructose by enzyme sorbitol dehydrogenase (SDH) with NAD + as a cofactor.
Consumption of NADPH reduces glutathione (GSH) reductase activity that its regeneration is dependent on NADPH. On the other hand, GSH is known as an important scavenger of ROS.
In the literature, it was shown that overexpression of aldose reductase in diabetic mice resulted in increased atherosclerosis and reduction of glutathione [9]. Also, in an experiment performed in diabetic rats' eyes, reduction of GSH was observed in their lens due to over-expression of aldose reductase (9). It was reported that reduction in nitric oxide (NO) availability might result in reduction of cellular glutathionylation and therefore inducing ROS production in diabetic rats (9).  Increased AGEs level contributes to increased rate of lower limb amputation, heart failure, and mortality after ischemic events which seems to be mediated by reduction in the number of collateral vessels in angiogram of diabetic patients (9). In a cohort of diabetes and atherosclerosis in Maastricht (CODAM ( study, it has been found that the rs3134945 SNP of RAGE is associated with higher glucose levels in diabetics. As well, the G28S polymorphism of RAGE has shown to be associated with diabetic nephropathy (21). It was reported that RAGE promoter polymorphism and -374T/A variant have a protective effect against vascular complications (21).

Protein kinase C activation pathway
PKCs

Glutathione peroxidase
GPx is a seleno enzyme that exists within the cell and is involved in converting hydrogen There was also no association between this SNP and diabetic neuropathy (DN) (2, 6).

Catalase
Catalase is a tetrameric hemoprotein which catalyzes the breakdown of H2O2 to H2O and O2. Heterozygote form of -21T/A polymorphism of catalase has also been found to increase the risk of T2DM in north Indians (2).

Glutathione S transferase
A decrease in GSH level in diabetic patients would make the cells more sensitive to oxidative stress because GSH plays a role against oxidative stress by scavenging free radicals and reactive oxygen intermediates (28). In South Iranian population, the null genotype of GSTM1 was found to be associated with T2DM but neither GSTT1 nor GSTP1 were shown to be associated with the disease. yet, the combination of GSTM1-null and GSTT1-null genotype showed the increased risk of developing T2DM (29  In addition, eNOS haplotype has shown association with retinopathy in T1DM (37), but the association was controversial in T2DM (38,39).
Although 'a' allele of eNOS polymorphisms has shown a significant association with neuropathy in T2DM, but the association was more significant in diabetic patients who had no other complications (39). Chinese population, showed a significant difference in allele and genotype frequencies (2). Two metaanalyses showed that the C allele of C47T polymorphism (rs4880) of SOD2 gene was significantly associated with reduced risk of DM; type 1 and T2DM, DN, diabetic neuropathy, and DR (53, 57) (Table 1).

Conclusions
Altogether, it has been shown that genetic markers can be used in the prediction and diagnosis

Conflict of interests
The authors declared that they have no competing interests.